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Claudin-6 enhances the malignant progression of gestational trophoblastic neoplasm by promoting proliferation and metastasis

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Abstract

Purpose

Choriocarcinoma (CC) is a rare and highly malignant epithelial tumour. However, the mechanism underlying its occurrence and development remains unknown. We aimed to reveal the biological significance and prognostic value of Claudin-6 (CLDN6) in gestational trophoblastic disease (GTD).

Patients and methods

We collected clinical GTD specimens from 2011 to 2019 and measured CLDN6 gene expression by immunohistochemistry (IHC). High-throughput mRNA sequencing (RNA-seq) revealed a GTD progression-associated gene. CCK-8, wound healing, and flow cytometry assays were used to assess the biological effects of CLDN6 overexpression and knockdown. The medical records of 118 GTD patients from 2011 to 2019 were retrospectively analysed to identify correlations between CLDN6 expression and GTD patient clinical–pathological parameters; these correlations were analysed using the chi-square test and one-way ANOVA. Univariate logistic regression was used to analyse various prognostic parameters of patients with post-molar GTN.

Results

CLDN6 had the second highest fold change in gene expression between GTN and normal samples. CLDN6 was highly expressed in GTN tissues and CC cell lines, and silencing CLDN6 inhibited the proliferation and migration and promoted the apoptosis of CC cells. CLDN6 overexpression was significantly correlated with uterine size (p = 0.01) and ovarian cysts > 6 cm (p = 0.027), CLDN6 expression was significantly higher in HR-GTNs than in low-risk GTNs (LR-GTNs) (p = 0.008), and logistic regression analysis showed that CLDN6 expression in hydatidiform moles (HMs) was related to a high risk of developing post-molar GTN (OR = 2.393, p = 0.03).

Conclusion

We propose that CLDN6 participates in the development of GTD and may become a new therapeutic target for CC.

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Data availability

All the data in our study will be made available by the authors upon reasonable request (addressed to Yifeng Wang).

Abbreviations

CC:

Choriocarcinoma

HR-GTN:

High-risk gestational trophoblastic neoplasm

CLDN6:

Claudin-6

GTD:

Gestational trophoblastic disease

IHC:

Immunohistochemistry

RNA-seq:

RNA sequencing

LR-GTNs:

Low-risk GTNs

DEGs:

Differentially expressed genes

rHMs:

Hydatidiform moles that regressed

FIGO:

International Federation of Obstetrics and Gynecology

cHMs:

Complete HMs

STR:

Short tandem repeat

MEM:

Minimum essential medium

RPMI:

Roswell Park Memorial Institute

IRS:

Immunoreactive score

IC50:

Half-maximal inhibitory concentration values

GO:

Gene ontology

shCLDN6/CLDN6-OV:

CLDN6 overexpression or downregulation

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Funding

This study was funded by the Natural Science Foundation of Fujian Province (2021j01409), Science and Technology Project of Health Commission of Fujian Province (2021CX0101) and Joint Funds for the Innovation of Science and Technology, Fujian province (2020y9155).

Author information

Author notes

  1. Qibin Wu and Meilian Peng have contributed equally to this work.

Authors and Affiliations

  1. Department of Gynecology, Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China

    Qibin Wu & Yifeng Wang

  2. Department of Gynecology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China

    Qibin Wu, Meilian Peng, Chengyu Lv, Tianfu Lin & Pengming Sun

  3. Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, People’s Republic of China

    Lihua Chen

  4. Laboratory of Gynecologic Oncology, Department of Gynecology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China

    Xiaodan Mao

  5. Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fuzhou, People’s Republic of China

    Xiaodan Mao & Pengming Sun

Authors
  1. Qibin Wu
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  2. Meilian Peng
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  8. Yifeng Wang
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Contributions

Conceptualization: QW, YW; Methodology: MP, TL, LC; Formal analysis and investigation: MP, CL, XM, Writing–original draft preparation: MP; Writing–review and editing: QW; Funding acquisition: QW; Resources: PS, YW; Supervision: PS, YW.

Corresponding authors

Correspondence to Pengming Sun or Yifeng Wang.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University (FMCH2021KRD020).

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Informed consent was obtained from all the patients.

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Wu, Q., Peng, M., Lv, C. et al. Claudin-6 enhances the malignant progression of gestational trophoblastic neoplasm by promoting proliferation and metastasis. Clin Transl Oncol 25, 1114–1123 (2023). https://doi.org/10.1007/s12094-022-03021-4

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  • DOI: https://doi.org/10.1007/s12094-022-03021-4

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